The overall objective of the proposed research is to elucidate the role of the DDR2 receptor (discoidin domain receptor 2) in stellate cell activation and hepatic fibrosis. In progressive fibrosis stellate cells undergo an activation in which they proliferate and synthesize a "scar" matrix rich in type I collagen. Although tyrosine kinase (RTK), 'DDR2', has been cloned from activated stellate cells by degenerate PCR. DDR2 has the unique feature of signaling in response to type I collagen rather than a peptide growth factor, unlike other RTKs. The Hypotheses are: 1) Stellate cell activation is perpetuated by DDR2 signaling in response to type I collagen. 2) Loss of DDR2 responses in stellate cells will diminish their activation and attenuate hepatic fibrosis. The Specific Aims to test these hypotheses are: 1. To characterize DDR2 expression in vivo in experimental and human liver injury. 2. To explore how extracellular matrix modulates DDR2 expression in cultured rat stellate cells. 3. To characterize cellular events following DDR2 signaling in stellate cells. 4. To assess the importance of DDR2 in hepatic fibrosis using DDR2 knockout mice. The experiments are a direct extension of earlier work in the laboratory elucidating the role of RTKs in stellate cell activation, and are immediately relevant to the pathogenesis of cirrhosis in patients with chronic liver injury and fibrosis. The findings could lead to new treatments for this debilitating and incurable condition.